Chronic pain has been recognized as an underserved area of medicine. Clinical care and research are hampered by the lack of objective correlates for the subjective complaint of pain. This is especially a problem for neuropathic pain patients, where the pain is caused by malfunction of the pain-sensing neurons, rather than injury to the area where the pain is felt. In this translational project we will evaluate two types of objective evidence of neural damage to see whether they correlate with the complaint of pain. We will investigate the usefulness of these methods in adults with one of two common neuropathic pain conditions, postherpetic neuralgia (PHN) after shingles (herpes zoster), or painful neuropathy in the lower legs from diabetes mellitus, and in rat models of these conditions. Data from individuals with and without pain will be compared. We will evaluate the usefulness of tests of specific sensory functions, using standardized quantitative sensory stimuli, for predicting who does or does not have pain from shingles or diabetes. We will also evaluate the usefulness of a new technique, counting the density of pain-sensing (nociceptive) nerve endings within the epiderrnal layer of small skin punch biopsies. Surprisingly, work by our group and others show that neuropathic pain patients usually have fewer nociceptive nerve endings in painful skin. When the amount of signal coming in from the periphery decreases, pain-processing neurons in the brain and spinal cord become hyperactive. The result can be pain in the absence of tissue injury. This is similar to the development of tinnitus (ringing in the ears) when people lose hearing. Our data suggests that after shingles, PEN pain is felt by only those patients whose density of nociceptive nerve endings has been reduced below a threshold value (650 neurites/mm2 skin surface area). In Specific Aim I, we will study patients about 6 weeks after onset of shingles with quantitative sensory testing and skin biopsies, and repeat them 6 months later. We will evaluate whether data from the first set of tests, or changes between the two test sessions, can provide a marker for those who recover from pain or not. In Specific Aim II we will compare sensory testing and skin biopsy data from normal people and diabetics with and without pain to see whether there is evidence for a threshold value separating individuals with and without pain, and whether we can identify a presymptomatic state. In Specific Aim III, we plan to evaluate sensory function of the paw in rat models of pain after sciatic nerve injury. At sacrifice, biopsies will be taken from the bottom of the rat's paws as well as from the injured nerves to see whether changes in the density of nociceptive nerve endings in the foot correlate with severity of damage in the nerve and with the rat's behavior during sensory testing. The goal of this research is to improve medical care for patients with chronic neuropathic pain, and facilitate research by identifying "biomarkers" that can be used as surrogate measures for the presence of neuropathic pain.